III. “META-METHODOLOGY” …about methods of systems medicine…

PHILOSOPHY AND HISTORY

OF (SYSTEMIC) MOLECULAR BIOSCIENCE AND MEDICINE

-  some interesting issues –

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ISSUES OF PHILOSOPHY AND HISTORY OF MOLECULAR BIOSCIENCE

(comp. Systems Biology – Philosophical foundations. Boogerd et al. 2007) - no explicit methodology, i.e. epistemic concept for technology-driven research - not deeper consideration of the multi-level problem ( different spatial & time scales; “emergence”: a cell is not a tissue, a tissue is not an organ, an organ is not an organism…) -  component-centered approach (proteins in the blood as bio-markers) versus a (mechanistic) interaction-centered multi-level approach -  reductionistic pre-assumptions that mostly remain implicit ( ignored brain-mind problem) -  poor conceptual analysis (“Information”, “Signal”…)

- Ethical issues integrated? (“participatory”: but well-known information asymmetry between patient and doctor, problem of probabilistic reasoning...)? 2

PHILOSOPHY OF SYSTEMS BIOLOGY (see D. Noble, “Music of Life” 2006) 1. no cell without environment (contextualization) 2. the cell has the potential for everything, but for actualization it needs the environment 3. the core-unit of the cell (nucleus, DNA) is nothing without the cytoplasm and organelles etc. and the membrane (internal environment) 4. no cell without a membrane (boundary condition) 5. no uni-directional causation, but (bidirectional) interaction 6. no only linear causation, but “circular” causation 7. cells are multi-level systems 8. processes are determined by multifactorial conditions 9. processes have multimodal effects 10. simple input-output models are not appropriate (internal loops of action, “feedback models”!)

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III.1 CONCEPTS

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DIFFERENTIAL KEY CONCEPTS:

„NETWORKS“ OR „SYSTEMS“ ?

-  particle-oriented or system-oriented ?

(Make it clear, but don‘t separate it !)

=> Cell as a molecular system / network ..

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DEFINITIONS – EPISTEMOLOGICAL ASPECTS System: - Is a structured entity / whole - „A set of a set of elements and a set of relations.“ (comp. Hall & Fagen ....) - Biosystem has (observation-dependent) boundaries that demarcate the system as a structured entity from the (its) environment (Miller, v. Foerster, Luhmann, ...) - circular causality is significant for living systems

Network: - „A network is a set of objects (called nodes or vertices) that are connected together“

Discussion: -  very similar mathematical definitions -  A “system“ can be understood as a structured entity (or wholeness) that is analysed by a top-down procedure, whereas a „network“ can be seen as an element-centred, search for connectivity (bottom-up procedure), - should be defined in the specific context

GENE

mRNA

Effects

PROTEIN

6 BIDIRECTIONAL, NOT ONLY UNIDIRCETIONAL FLOW OF „INFORMATION“ ?

- Since the 1950s bottom-up causality, now „Epigenetics“...

Determination (with modulation) Watson & Crick 1953

Feedbacks of end product Jacob & Monod 1959

GENE

mRNA

PROTEIN

Effects

GENE

mRNA

PROTEIN

Effects

DETERMINISM OR LIMITATIONS BY GENES ?

-  left index finger prints of identical twins are different -  postranslational modifications in proteins are not directly

controlled by genes -  „E-lytes“ (sodium, potassium, calcium and chloride) are

essential for cellular function; their (relative) intracellular concentrations are not controlled by genes but they modify intracellular processes

-  electrical voltage modulates activity / reactivity of proteins and vice versa (e.g. neurons)

-  Transcription factors control expression of genes.. -  Environment acts via epigenetic factors transgenerationally....

(Cortisol...) -  occurence of many diseases is modified by environmental and

life-style factors (twin studies / adoption studies..) -  etc.

=> Genes are necessary but not sufficient condition of mammalian life / „functions“....

MOLECULAR SYSTEMS MEDICINE - Not so new for students of medicine....-

Michal 1974, Böhringer, Mannheim 8

FROM CELL TOWARDS ORGANISMIC SYSTEMS BIOLOGY - nested causal loops -

(s. Laubichler & Müller, Vienna)

III.2 EPISTEMIC PROCESS

-  Dialetics of “empirics” and theory –

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!

http://www.meduniwien.ac.at/msi/biosim/omics2bedside.html

RESEARCH METHODOLOGY OF SYSTEMS MEDICINE Vienna Group of Computational Systems Medicine

many disorders / one gene

one disorder / many genes

Many disorders / many genes

CAUSALITY ANALYSIS – PHENOTYPE / GENOTYPE possible causal realations

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III.3 MODELLING

- from data and “educated guess” to formal models –

(exploratory modelling by simulation experiments)

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Time

Intensity

DATA ANALYSIS OF TIME SERIES – how can curves be approximated best? -

y = sin (x) Caveat: AM

y = ??? f (x) Tretter 2005

5 10 15 20 25 30

-10

-5

5

10

Time course of x-variable of Lorenz-Attractor

pendulum positions

DOUBLE PENDULUM – chaotic patterns of the spatial position of 2 coupled elements -

(Wolfram, Mathematica 2009) asynchrony synchrony

2^9 = 512

DATA COMPLEXITY – possible on-off patterns of a network -

2^16 = 65536 2^25 = 33.554.432

Data sets from high-throughput technologies (DNA microarrays) and „pattern detection“ for pathology…millions of data points... Only machines „understand“ the relations..and detect classes by multivariate statistics (PCA, CA, DA..) and graph theroy etc.?

ANALYSIS OF COMPLEX GRAPHS

In search of elementary 4-component modules („motifs“ U. Alon 2007) 199 such modules are possible =>

DOPAMINE GLUTAMATE

CaMII

CaAdenylylcyclase 5

pThr75DARPP32

pThr34

PKA

cAMP CaM

PP2A PP2B

NMDA receptorD1receptor

D2receptor

PP1

PDE1

11

112

2 22

3

33

34

3 4

4

6

5

4

3

Loop with 2 inhibitions=> switch ?

et al:

From: Lindskog et al. 2006

Dopamine PKAcAMPDopamine PKAcAMP

Signaling pathway

SIMULATION FUNCTION ANALYSIS OF SUBCELLULAR MOLECULAR

NETWORKS

Structure and processes in intracellular molecular networks

- puls-/ ramp-/ sawtooth functions

Dopamine input and intracellular signal transduction

Epistemic objects: Real systems as demarcated structures with substructures & suprastructures Concepts: System, Element, Structure; Network.....Perturbation / Stimulation.. Constructs: Non-equilibrium as a principle of life, control loop, „Teufelskreis“ Self organization…circular causality... Methods: From the list to the network, modelling methodology, heuristic value of computer simulations,... Theories: Theory of regulation, Information theory, Catastrophe theory, Chaos theory, Complexity theory 19

SYSTEMS MEDICINE: STRUCTURED APPLICATION OF SYSTEMS SCIENCE (L.v. Bertalanffy, BCSSS; „System Dynamics“ group-MIT; J. Sterman)

SYSTEMS MEDICINE, if based on SYSTEMS SCIENCE: (Systems scientific medicine => „psycho-social“ systems medicine; F. Tretter) Explicit problem-centred issues and assumptions: - hierarchical view regarding organization of living systems (cell is the atom of an organism, not the genome; J.G. Miller) - Selective boundary function (buffering / loose coupling) is constitutive (Luhmann) -  Decent non-equilibrium as driver of health (difference between internal and external world; Prigogine) -  circular causality and operational closedness (Jacob & Monod, v. Foerster) -  self-organization as basic principle (Ashby, Eigen & Schuster) - coherence of coupled intra-level und inter-level processes -  embedded in bio-psycho-social theories of health and disease -  „Complexity“ of structure and processes (Mainzer) -  Non-linearity of „dynamics“ / processes (an der Heiden) -  Network in system: Convergence and divergence, (lateral) interaction and loops of pathways and action / processes (Alon)

SUMMARY III - META-METHODOLOGY OF SYSTEMS MEDICINE => (non-reductive) systems medicine is needed! * developing organismic, psycho-social, clinical systems medicine -  be aware of epistemological traps -  define concepts precisely (complexity...) -  conceptualize the epistemic object as a living system! -  develop methodology (of modelling) -  develop theoretical concepts and models